Immunomodulatory role of Emblica officinalis in arsenic induced oxidative damage and apoptosis in thymocytes of mice.
Arsenic is widely distributed in the environment and has been found to be associated with the various health related problems including skin lesions, cancer, cardiovascular and immunological disorders. The fruit extract of Emblica officinalis (amla) has been shown to have anti-oxidative and immunomodulatory properties. In view of increasing health risk of arsenic, the present study has been carried out to investigate the protective effect of amla against arsenic induced oxidative stress and apoptosis in thymocytes of mice. Mice were exposed to arsenic (sodium arsenite 3 mg/kg body weight p.o.) or amla (500 mg/kg body weight p.o.) or simultaneously with arsenic and amla for 28 days. The antioxidant enzyme assays were carried out using spectrophotometer and generation of ROS, apoptotic parameters, change in cell cycle were carried out using flow cytometer following the standard protocols. Arsenic exposure to mice caused a significant increase in the lipid peroxidation, ROS production and decreased cell viability, levels of reduced glutathione, the activity of superoxide dismutase, catalase, cytochrome c oxidase and mitochondrial membrane potential in the thymus as compared to controls. Increased activity of caspase-3 linked with apoptosis assessed by the cell cycle analysis and annexin V/PI binding was also observed in mice exposed to arsenic as compared to controls. Co-treatment with arsenic and amla decreased the levels of lipid peroxidation, ROS production, activity of caspase-3, apoptosis and increased cell viability, levels of antioxidant enzymes, cytochrome c oxidase and mitochondrial membrane potential as compared to mice treated with arsenic alone. The results of the present study exhibits that arsenic induced oxidative stress and apoptosis significantly protected by co-treatment with amla that could be due to its strong antioxidant potential.


Temporal patterns in the acoustic signals of beaked whales at Cross Seamount.
Seamounts may influence the distribution of marine mammals through a combination of increased ocean mixing, enhanced local productivity and greater prey availability. To study the effects of seamounts on the presence and acoustic behaviour of cetaceans, we deployed a high-frequency acoustic recording package on the summit of Cross Seamount during April through October 2005. The most frequently detected cetacean vocalizations were echolocation sounds similar to those produced by ziphiid and mesoplodont beaked whales together with buzz-type signals consistent with prey-capture attempts. Beaked whale signals occurred almost entirely at night throughout the six-month deployment. Measurements of prey presence with a Simrad EK-60 fisheries acoustics echo sounder indicate that Cross Seamount may enhance local productivity in near-surface waters. Concentrations of micronekton were aggregated over the seamount in near-surface waters at night, and dense concentrations of nekton were detected across the surface of the summit. Our results suggest that seamounts may provide enhanced foraging opportunities for beaked whales during the night through a combination of increased productivity, vertical migrations by micronekton and local retention of prey. Furthermore, the summit of the seamount may act as a barrier against which whales concentrate prey.


Diels-Alder reaction for tumor pretargeting: in vivo chemistry can boost tumor radiation dose compared with directly labeled antibody.
Current pretargeting systems use noncovalent biologic interactions, which are prone to immunogenicity. We previously developed a novel approach based on the bioorthogonal reaction between a radiolabeled tetrazine and an antibody-conjugated trans-cyclooctene (TCO). However, the tumor-to-blood ratio was low due to reaction with freely circulating antibody-TCO. Here we developed 2 tetrazine-functionalized clearing agents that enable rapid reaction with and removal of a TCO-tagged antibody (CC49) from blood. Next, we incorporated this approach into an optimized pretargeting protocol in LS174T-bearing mice. Then we compared the pretargeted (177)Lu-labeled tetrazine with (177)Lu-labeled CC49. The biodistribution data were used for mouse and human dosimetry calculations. The use of a clearing agent led to a doubling of the tetrazine tumor uptake and a 125-fold improvement of the tumor-to-blood ratio at 3 h after tetrazine injection. Mouse dosimetry suggested that this should allow for an 8-fold higher tumor dose than is possible with nonpretargeted radioimmunotherapy. Also, humans treated with CC49-TCO-pretargeted (177)Lu-tetrazine would receive a dose to nontarget tissues 1 to 2 orders of magnitude lower than with directly labeled CC49. The in vivo performance of chemical pretargeting falls within the range of results obtained for the clinically validated pretargeting approaches in mice, with the advantage of potentially allowing for fractionated radiotherapy as a result of a lower likelihood of immunogenicity. These findings demonstrate that biologic pretargeting concepts can be translated to rapid bioorthogonal chemical approaches with retained potential.


Expression of functional beta 2-adrenergic receptors in a rat airway epithelial cell line (SPOC1) and cell density-dependent induction by glucocorticoids.
The beta 2-adrenergic receptor (beta 2AR) signal transduction system regulates many key functions of airway epithelium. In this study, we have pharmacologically characterized the beta 2AR and determined the impact of glucocorticoids on beta 2AR gene transcription in SPOC1 cells, a continuous cell line derived from the tracheal epithelium of rats. [125I]Cyanoiodopindolol assays demonstrated that binding to SPOC1 cell membranes was saturable (Bmax = 62.6 +/- 6 fmol/mg protein) and of high affinity (Kd = 6.3 +/- 0.8 pM). From competition experiments, the rank order of potency of agonists (isoproterenol > epinephrine >> norepinephrine) and the high affinity (Ki = 0.37 +/- 0.05 nM) of the beta 2-selective antagonist ICI 118,551 suggested the predominance of the beta 2AR subtype. Two isoforms of the alpha subunit of Gs (45 and 52 kDa) were identified by Western blot analysis. Isoproterenol-stimulated cyclic AMP levels increased in a dose-dependent manner, confirming that SPOC1 cell beta 2ARs are functionally coupled to adenylyl cyclase. The effect of glucocorticoids on beta 2AR expression was assessed in radioligand and transient transfection assays. Dexamethasone treatment of SPOC1 cells increased both beta 2AR protein and beta 2AR-luciferase fusion gene expression 1.6- to 3.1-fold, with the greatest increase demonstrated in cells cultured at low density compared to cells grown at high density.


An Electrochemical Sensor of Theophylline on a Boron-Doped Diamond Electrode Modified with Nickel Nanoparticles.
Theophylline is a drug with a narrow therapeutic range. Electrochemical sensors are a potentially effective method for detecting theophylline concentration to prevent toxicity. In this work, a simple modification of a boron-doped diamond electrode using nickel nanoparticles was successfully performed for a theophylline electrochemical sensor. The modified electrode was characterized using a scanning electron microscope and X-ray photoelectron spectroscopy. Square wave voltammetry and cyclic voltammetry methods were used to study the electrochemical behavior of theophylline. The modified nickel nanoparticles on the boron-doped diamond electrode exhibited an electrochemically active surface area of 0.0081 cm2, which is larger than the unmodified boron-doped diamond's area of 0.0011 cm2. This modified electrode demonstrated a low limit of detection of 2.79 µM within the linear concentration range from 30 to 100 µM. Moreover, the modified boron-doped diamond electrode also showed selective properties against D-glucose, ammonium sulfate, and urea. In the real sample analysis using artificial urine, the boron-doped diamond electrode with nickel nanoparticle modifications achieved a %recovery of 105.10%, with a good precision of less than 5%. The results of this work indicate that the developed method using nickel nanoparticles on a boron-doped diamond electrode is promising for the determination of theophylline.


Negative elongation factor accelerates the rate at which heat shock genes are shut off by facilitating dissociation of heat shock factor.
Promoter-proximal pausing of RNA polymerase II (Pol II) occurs on thousands of genes in animal cells. This pausing often correlates with the rapid induction of genes, but direct tests of the relationship between pausing and induction rates are lacking. hsp70 and hsp26 in Drosophila are rapidly induced by heat shock. Contrary to current expectations, depletion of negative elongation factor (NELF), a key factor in setting up paused Pol II, reduced pausing but did not interfere with rapid induction. Instead, depletion of NELF delayed the time taken for these genes to shut off during recovery from heat shock. NELF depletion also delayed the dissociation of HSF from hsp70 and hsp26, and a similar delay was observed when cells were depleted of the histone acetyltransferase CBP. CBP has been reported to associate with Pol II, and acetylation of HSF by CBP has been implicated in inhibiting the DNA-binding activity of HSF. We propose that NELF-mediated pausing allows Pol II to direct CBP-mediated acetylation of HSF, thus causing HSF to dissociate from the gene. Activators are typically viewed as controlling Pol II. Our results reveal a possible reciprocal relationship in which paused Pol II influences the activator.


Novel sequence variants in the TMC1 gene in Pakistani families with autosomal recessive hearing impairment.
Though many hearing impairment genes have been identified, only a few of these genes have been screened in population studies. For this study, 168 Pakistani families with autosomal recessive hearing impairment not due to mutations in the GJB2 (Cx26) gene underwent a genome scan. Two-point and multipoint parametric linkage analyses were carried out. Twelve families had two-point or multipoint LOD scores of 1.4 or greater within the transmembrane cochlear expressed gene 1 (TMC1) region and were subjected to further screening with direct DNA sequencing. Five novel putatively functional non-synonymous sequence variants, c.830A>G (p.Y277C), c.1114G>A (p.V372M), c.1334G>A (p.R445H), c.2004T>G (p.S668R), and c.2035G>A (p.E679K), were found to segregate within seven families, but were not observed in 234 Pakistani control chromosomes. The variants c.830A>G (p.Y277C), c.1114G>A (p.V372M), and c.1334G>A (p.R445H) occurred at highly conserved regions and were predicted to lie within hydrophobic transmembrane domains, while non-synonymous variants c.2004T>G (p.S668R) and c.2035G>A (p.E679K) occurred in extracellular regions that were not highly conserved. There is evidence that the c.2004T>G (p.S668R) variant may have occurred at a phosphorylation site. One family has the known splice site mutation c.536 -8T>A. The prevalence of non-syndromic hearing impairment due to TMC1 in this Pakistani population is 4.4% (95%CI: 1.9, 8.6%). The TMC1 protein might have an important function in K(+) channels of inner hair cells, which would be consistent with the hypothetical structure of protein domains in which sequence variants were identified.


The challenge of converting Gram-positive-only compounds into broad-spectrum antibiotics.
Multidrug resistant Gram-negative bacterial infections are on the rise, and there is a lack of new classes of drugs to treat these pathogens. This drug shortage is largely due to the challenge of finding antibiotics that can permeate and persist inside Gram-negative species. Efforts to understand the molecular properties that enable certain compounds to accumulate in Gram-negative bacteria based on retrospective studies of known antibiotics have not been generally actionable in the development of new antibiotics. A recent assessment of the ability of >180 diverse small molecules to accumulate in Escherichia coli led to predictive guidelines for compound accumulation in E. coli. These "eNTRy rules" state that compounds are most likely to accumulate if they contain a nonsterically encumbered ionizable Nitrogen (primary amines are the best), have low Three-dimensionality (globularity ≤ 0.25), and are relatively Rigid (rotatable bonds ≤ 5). In this review, we look back through 50+ years of antibacterial research and 1000s of derivatives and assess this historical data set through the lens of these predictive guidelines. The results are consistent with the eNTRy rules, suggesting that the eNTRy rules may provide an actionable and general roadmap for the conversion of Gram-positive-only compounds into broad-spectrum antibiotics.


Impact of witnessing death on hospice patients.
In the three decades since the concept of "awareness" was introduced to describe the nature of communication between dying people and their carers, there has been a radical change in hospital policies and medical practice. It is now common for the majority of cancer patients to be given full information about their disease and prognosis. Hospices provide a model of care in which death and dying are dealt with in an open manner. While this approach has been welcomed by the majority of people, a minority might still prefer a more limited awareness. An inevitable part of hospice care is the exposure to, and awareness of, people who are dying. There is little empirical data that considers the impact of death on fellow patients. This pilot investigation compared psychological morbidity, perceptions of comfort and/or distress, and descriptions of a "good death" in hospice cancer patients who reported witnessing a fellow patient's death (n = 34) with patients who did not have this experience (n = 33). Patients were assessed using the Hospital Anxiety and Depression scale, an Events Checklist and a semi-structured interview. The results indicate that patients witnessing a death were significantly less depressed than those who did not. Awareness of dying was found to be both comforting and distressing, although overall patients reported more comforting than distressing events. A "good death" was defined by patients in terms of symptom control, including dying in their sleep, being pain free, quietness and dignity. Narratives were used to describe the meaning of a "good death". Quantitative and qualitative analyses have been undertaken to provide a complex interpretation of these issues.


A Descriptive Analysis of Care Provided by Law Enforcement Prior to EMS Arrival in the United States.
Study Objectives Law enforcement is increasingly viewed as a key component in the out-of-hospital chain of survival, with expanded roles in cardiac arrest, narcotic overdose, and traumatic bleeding. Little is known about the nature of care provided by law enforcement prior to the arrival of Emergency Medical Services (EMS) assets. The purpose of the current study was to perform a descriptive analysis of events reported to a national EMS database. This study was a descriptive analysis of the 2014 National Emergency Medical Services Information System (NEMSIS) public release research data set, containing EMS emergency response data from 41 states. Code E09_02 1200 specifically identifies care provided by law enforcement prior to EMS arrival. A total of 25,835,729 unique events were reported. Of events in which pre-arrival care was documented, 2.0% received prior aid by law enforcement. Patients receiving law enforcement care prior to EMS arrival were more likely to be younger (52.8 [SD=23.3] years versus 58.7 [SD=23.3] years), male (54.8% versus 46.7%), and white (80.3% versus 77.5%). Basic Life Support (BLS) EMS response was twice as likely in patients receiving prior aid by law enforcement. Multiple-casualty incidents were five times more likely with prior aid by law enforcement. Compared with prior aid by other services, law enforcement pre-arrival care was more likely with motor vehicle accidents, firearm assaults, knife assaults, blunt assaults, and drug overdoses, and less likely at falls and childbirths. Cardiac arrest was significantly more common in patients receiving prior aid by law enforcement (16.5% versus 2.6%). Tourniquet application and naloxone administration were more common in the law enforcement prior aid group. Where noted, law enforcement pre-arrival care occurs in 2.0% of EMS patient encounters. The majority of cases involve cardiac arrest, motor vehicle accidents, and assaults. Better understanding of the nature of law enforcement care is required in order to identify potential barriers to care and to develop appropriate training and policy recommendations. Klassen AB , Core SB , Lohse CM , Sztajnkrycer MD . A descriptive analysis of care provided by law enforcement prior to EMS arrival in the United States. Prehosp Disaster Med. 2018;33(2):165-170.


Protein-based materials: from sources to innovative sustainable materials for biomedical applications.
Proteins display an essential role in numerous natural systems due to their structural and biological properties. Given their unique properties, proteins have been thoroughly investigated in the last few decades, offering a myriad of solutions for the development of innovative biomaterials, including films, foams, composites and gels, in particular for biomedical applications such as drug delivery systems, biosensors and scaffolds for tissue regeneration. In this context, this review intends to give a general overview of the potential of protein based materials within the sustainable polymers context, covering aspects ranging from protein types, selection/isolation to properties of protein based (nano)materials and biomedical applications, passing through preparation methodologies of materials.


Sensorineural hearing loss in experimental purulent otitis media due to Streptococcus pneumoniae.
Sensorineural hearing loss (SNHL) has been described clinically following chronic otitis media with effusion, but to the best of our knowledge, no studies have demonstrated SNHL in an animal model of otitis media. Using the chinchilla model of pneumococcal otitis media, significant SNHL was demonstrated after purulent otitis media, especially at higher frequencies. Animals with otitis media received penicillin G procaine treatment for five days after otitis media with effusion (OME) was first documented; resolution of middle ear infection was confirmed by middle ear effusion culture in all animals. Both the inoculated and uninoculated ears were examined by tone burst-elicited compound action potential at threshold. The inoculated ear showed a marked hearing loss of 13 to 36 dB three to four days after OME was first documented; a hearing loss up to 24 dB persisted two to five weeks after inoculation. The change in the compound action potential was highly significant at all frequencies studied. Conductive losses were largely ruled out because there was no middle ear effusion at death and the tympanogram was normal. Purulent labyrinthitis was ruled out by histopathological study. These results indicate that purulent pneumococcal otitis media in the chinchilla model causes significant SNHL and suggest that the pathogenesis of SNHL associated with chronic OME in humans may be studied in this model.


Intra-uterine Infection with Babesia bovis in a 2-day-old Calf.
Infection with Babesia bovis was diagnosed in a 2-day-old female calf apparently transmitted in utero. The calf was born as the second calving to a cross-bred beef cow permanently on pasture. Diagnosis was based upon identification of B. bovis in peripheral blood smears and clinical signs which included fever, jaundice, pale mucous membranes and convulsions. Anaemia, leucocytosis, thrombocytopenia and lymphocytosis were noted at the febrile acute stage of the disease. The blood smears revealed evidence of regeneration of toxic neutrophils with a left shift, severe spherocytosis and high degree of basophilic stippling. Elevated concentration of aspartate aminotransferase, lactate dehydrogenase, and creatine kinase were also noted, and were probably the result of haemolysis, dehydration and muscle damage because of recumbancy. Elevated total bilirubin concentration following haemolysis resulted in jaundice. The neurological symptoms observed were probably caused by sludging of parasitized erythrocytes in the brain capillaries. The calf recovered following treatment with diminazene aceturate and the recovery was followed up clinically, haematologically and biochemically.


Efficacy of muscle exercise in patients with muscular dystrophy: a systematic review showing a missed opportunity to improve outcomes.
Although muscular dystrophy causes muscle weakness and muscle loss, the role of exercise in the management of this disease remains controversial. The purpose of this systematic review is to evaluate the role of exercise interventions on muscle strength in patients with muscular dystrophy. We performed systematic electronic searches in Medline, Embase, Web of Science, Scopus and Pedro as well as a list of reference literature. We included trials assessing muscle exercise in patients with muscular dystrophy. Two reviewers independently abstracted data and appraised risk of bias. We identified five small (two controlled and three randomized clinical) trials comprising 242 patients and two ongoing randomized controlled trials. We were able to perform two meta-analyses. We found an absence of evidence for a difference in muscle strength (MD 4.18, 95% CIs - 2.03 to 10.39; p = 0.91) and in endurance (MD -0.53, 95% CIs -1.11 to 0.05; p = 0.26). In both, the direction of effects favored muscle exercise. The first included trial about the efficacy of muscular exercise was published in 1978. Even though some benefits of muscle exercise were consistently reported across studies, the benefits might be due to the small size of studies and other biases. Detrimental effects are still possible. After several decades of research, doctors cannot give advice and patients are, thus, denied basic information. A multi-center randomized trial investigating the strength of muscles, fatigue, and functional limitations is needed.


Non-invasive Coronary Artery Disease Screening Based on Electrocardiogram Characteristics and Clinical Risk Factors.
Coronary artery disease (CAD), an acute and life-threatening cardiovascular disease, is a leading cause of mortality and morbidity worldwide. Coronary angiography, the principal diagnostic tool for CAD, is invasive, expensive, and requires a lot of skilled effort. The current study aims to develop an automated and non-invasive CAD detection model and improve its performance as closely as possible to clinically acceptable diagnostic sensitivity. Electrocardiogram (ECG) characteristics are observed to be altered due to CAD and can be studied to develop a screening tool for its detection. The subject's clinical information can help broadly identify the high-cardiac-risk population and serve as a primary step in diagnosing CAD. This paper presents an approach to automatically detect CAD based on clinical data, morphological ECG features, and heart rate variability (HRV) features extracted from short-duration Lead-II ECG recordings. A few popular machine-learning classifiers, including support vector machine (SVM), random forest (RF), K-nearest neighbours (KNN), Gaussian Naïve Bayes (GNB), and multi-layer perceptron (MLP), are trained on the extracted feature space, and their performance is evaluated. Classifiers built by integrating clinical data and features extracted from ECG recordings demonstrated better performance than those built on each feature set separately, and the RF classifier outperforms other considered machine learners and reports an average testing accuracy of 94% and a G-mean score of 92% with a 5-fold cross-validation training accuracy of 95(± 0.04)%.Clinical relevance- The proposed method uses a brief, single-lead ECG recording and performs similarly to current clinical practices in an explainable manner. This makes it suitable for deployment via wearable technology (like smart watch gadgets) and telemonitoring, which may facilitate an earlier and more widespread CAD diagnosis.


Obstetrical outcome valuations by patients, professionals, and laypersons: differences within and between groups using three valuation methods.
Decision-making can be based on treatment preferences of the patient, the doctor, or by guidelines based on lay people's preferences. We compared valuations assigned by three groups: patients, obstetrical care professionals, and laypersons, for health states involving both mother and (unborn) child. Our aim was to compare the valuations of different groups using different valuation methods and complex obstetric health outcome vignettes that involve both maternal and neonatal outcomes. Patients (n = 24), professionals (n = 30), and laypersons (n = 27) valued the vignettes using three valuation methods: visual analogue scale (VAS), time trade-off (TTO), and discrete choice experimentation (DCE). Each vignette covered five health attributes: maternal health ante partum, time between diagnosis and delivery, process of delivery, maternal outcome, and neonatal outcome. We used feasibility questionnaires, Generalization theory, test-retest reliability and within-group reliability to compare the valuation patterns between groups and methods. We assessed relative weights from each valuation method to test for consistency across groups. Test-retest reliability was equal across groups, but different across methods: highest for VAS (ICC = 0.61-0.73), intermediate for TTO (ICC = 0.24-0.74) and lowest for DCE (kappa = 0.15-0.37). Within-group reliability was highest in all groups with VAS (ICC = 0.70-0.73), intermediate with DCE (kappa = 0.56-0.76) and lowest with TTO (ICC = 0.20-0.66). Effects of groups were smaller than effects of methods. Differences between groups were largest for severe health states. Based on our results, decision making among laypersons should use TTO or DCE; patients should use VAS or TTO.


Pain prevalence in instrumental musicians: a systematic review.
To investigate current prevalence of pain among different musician groups, sex, and body region. Studies were sought from PubMed, Web of Science, Academic Search Complete, Science Direct, and Scielo. Databases were searched from 1 January 2000 until December 2012. Two reviewers screened titles and abstracts and assessed full reports for potentially eligible studies. One reviewer extracted information on musicians' characteristics, study methods, and study quality. When possible, a meta-analysis of pain prevalence estimates was performed. A total of 18 studies were included in this systematic review. Studies assessed pain prevalence in general and the prevalence of pain affecting playing capacity for different time periods: point, 1-week, 1-year, month, and lifetime prevalence. The prevalence of pain in general, across all groups of musicians and periods of interest over which pain was assessed, varied between 29.0 and 90.0%, whereas the prevalence of pain affecting playing capacity varied between 25.8 and 84.4%. There was a tendency for guitar players to have the highest pain prevalence. The most affected body regions were the low back (9.8 to 66.7%) and neck (9.8 to 48.5%). Pain prevalence is high among musicians, independent of the pain definition and time period used. Health and educational policy makers should become aware of the high prevalence of pain affecting performance practices, so that pain-associated mechanisms are investigated and preventive strategies are tested and implemented.


A method for extending AC susceptometry to long-timescale magnetic relaxation.
As the ability to generate magnetic anisotropy in molecular materials continues to hit new milestones, concerted effort has shifted towards understanding, and potentially controlling, the mechanisms of magnetic relaxation across a large time and temperature space. Slow magnetic relaxation in molecules is highly temperature-, field-, and environment-dependent with the relevant timescale easily traversing ten orders of magnitude for current single-molecule magnets (SMM). The prospect of synthetic control over the nature of (and transition probabilities between) magnetic states make unraveling the underlying mechanisms an important yet daunting challenge. Currently, instrumental considerations dictate that the characteristic relaxation time, τ, is determined by separate methods depending on the timescale of interest. Static and dynamic probe fields are used for long- and short-timescales, respectively. Each method captures a distinct, non-overlapping time range, and experimental differences lead to the possibility of fundamentally different meanings for τ being plotted and fitted globally as a function of temperature. Herein, we present a method to generate long-timescale waveforms with standard vibrating sample magnetometry (VSM) instrumentation, allowing extension of alternating current (AC) susceptometry to SMMs and other superparamagnets with arbitrarily long relaxation time. We fit these data to a generalized Debye model and present a comparison to results obtained from direct current (DC) magnetization decay.


Breast conserving therapy in stage I & II breast cancer in Korea.
A randomized clinical study of 187 patients with T1, T2 breast cancer was performed, in order to compare the effects of modified radical mastectomy (MRM) and breast conserving therapy (BCT) on breast recurrence, overall survival, and disease-free survival. One hundred eighty seven patients with T1, T2 breast cancer, admitted at Yongdong Severance Hospital from April 1991 to August 1994, were randomized into two different treatment groups. Of the 187 patients, 111 patients had received MRM and 76 had received BCT. In any of the variables considered with the exceptions of age and menopausal status, patient characteristics such as tumor size, incidence of axillary lymph node metastasis, histologic grading, and estrogen and progesterone receptor positive rate were not significantly different between the two groups (p < 0.05). Using the Kaplan-Meier Product-limit method and log-rank test, the difference of locoregional recurrence, and overall and disease-free survival, between these comparable groups was analyzed. Average follow-up period was 37.6 months. Two out of 111 MRM patients and two out of 76 BCT patients had locoregional recurrence. Only one patient who had MRM was found to have a recurrence in her opposite breast. The overall survival rates in MRM and BCT patients were, respectively 93.7% and 94.1%. Furthermore, the disease-free survival rates were, respectively, 89.2% and 93.9%. This result indicates that there were no significant differences between two groups in locoregional recurrence, and overall and disease-free survival. Having gained a better cosmetic appearance, the conservative treatment group was satisfied with the BCT. In this study, we conclude that BCT is a good alternative surgical treatment modality for T1, T2 Korean breast cancer patients, which could substitute for the more traditional MRM. However, further follow-up will be needed for long-term results.


[Formal genetic findings in attention-deficit/hyperactivity-disorder].
Twin, family and adoption studies have led to a solid understanding of the contribution of both genetic and environmental factors to the development of attention deficit/hyperactivity disorder (ADHD). We review recent studies under consideration of both methodological aspects and relevant findings. Heritability estimates in the range of 0.6 - 0.8 surpass those for most other child and adolescent psychiatric disorders. First degree relatives have elevated rates for ADHD, affective disorders, conduct disorders and substance abuse and dependency. The ADHD subtype of the index patient does not predict the subtype of other family members affected with ADHD; hence non-genetic factors seemingly account for this intrafamilial variability. Because the familial rates for ADHD are not higher in families of female in comparison to male index patients, there is no indication that the genetic loading is higher in affected females. Recently, rater effects have been discussed broadly: Whereas the heritability estimates are uniformly high independent of the informant (mother, father, teacher), the correlations between quantitatively rated symptoms are low between different informants. Knowledge of the formal genetic aspects of ADHD is a prerequisite for understanding the results of recent molecular genetic studies.


Detection of Dekkera-Brettanomyces strains in sherry by a nested PCR method.
Brettanomyces sp. and its ascosporogenous sexual state, Dekkera sp., have been well documented as spoilage microorganisms, usually associated with barrel-aged red wines. In this report, we describe the genetic characterization, on the basis of DNA content per cell, electrophoretic karyotyping, and mitochondrial DNA restriction patterns, of a Dekkera yeast strain isolated from sherries and of a number of other Brettanomyces and Dekkera strains. By using a genomic DNA fragment of the isolated Dekkera strain, we developed a two-step PCR method which directs the specific amplification of target DNA from this strain and from other Brettanomyces-Dekkera strains. The method efficiently amplified the target DNA from intact cells, obviating DNA isolation, and yielded a detection limit of fewer than 10 yeast cells in contaminated samples of sherry.


Genetic Control of Hemerythrin Specificity in a Marine Worm.
A biochemical polymorphism of coelomic hemerythrin has been found in the sipunculid Golfingia gouldii; the electrophoretically "fast" and "slow" coelomic hemerythrins differ in their oxygen equilibria and by a single peptide in tryptic and chymotryptic "fingerprints." All individuals of this sipunculid have the same vascular hemerythrin, which is electrophoretically different from any of the coelomic hemerythrins. Vascular and coelomic hemerythrins of another sipunculid, Dendrostomum cymodoceae, have quite different "fingerprints." Thus, on the basis of two separate types of evidence the tissue-specific hemerythrins appear to have a distinct genetic basis. The embryological and phylogenetic implications are discussed.


Hypersaline waters - a potential source of foodborne toxigenic aspergilli and penicillia.
Previous studies of hypersaline environments have revealed the dominant presence of melanized yeast-like fungi and related Cladosporium spp. In this study, we focused on the genera Aspergillus and Penicillium and their teleomorphic forms. From oligotrophic and eutrophic hypersaline waters around the world, 60 different species were identified, according to their morphological characteristics and extrolite profiles. For the confirmation of five new species, additionally, sequence analysis of the internal transcribed spacer region, the partial large subunit-rDNA and the partial β-tubulin gene was performed. The species Aspergillus niger, Eurotium amstelodami and Penicillium chrysogenum were detected with the highest frequencies at all of the sampled sites; thus, they represent the pan-global stable mycobiota in hypersaline environments. Possible candidates were also Aspergillus sydowii and Eurotium herbariorum, as they were quite evenly distributed among the sampled sites, and Aspergillus candidus, which was abundant, but more locally distributed. These species and their byproducts can accumulate downstream following evaporation of brine, and they can become entrapped in the salt crystals. Consequently, marine salt used for consumption can be a potential source of food-borne fungi and their byproducts. For example, ochratoxin-A-producing species Penicillium nordicum was recovered from brine, salt and salted meat products.


Forecasting and trading cryptocurrencies with machine learning under changing market conditions.
This study examines the predictability of three major cryptocurrencies-bitcoin, ethereum, and litecoin-and the profitability of trading strategies devised upon machine learning techniques (e.g., linear models, random forests, and support vector machines). The models are validated in a period characterized by unprecedented turmoil and tested in a period of bear markets, allowing the assessment of whether the predictions are good even when the market direction changes between the validation and test periods. The classification and regression methods use attributes from trading and network activity for the period from August 15, 2015 to March 03, 2019, with the test sample beginning on April 13, 2018. For the test period, five out of 18 individual models have success rates of less than 50%. The trading strategies are built on model assembling. The ensemble assuming that five models produce identical signals (Ensemble 5) achieves the best performance for ethereum and litecoin, with annualized Sharpe ratios of 80.17% and 91.35% and annualized returns (after proportional round-trip trading costs of 0.5%) of 9.62% and 5.73%, respectively. These positive results support the claim that machine learning provides robust techniques for exploring the predictability of cryptocurrencies and for devising profitable trading strategies in these markets, even under adverse market conditions.


Spontaneous rupture of the common bile duct.
Spontaneous rupture of the common bile duct in adults is very rare. The authors report only the 14th case in the Western literature. A 25-year-old woman had signs of peritonitis suggestive of a perforated appendix, but at operation the appendix appeared normal and a large amount of bile was found in the peritoneal cavity. A 2-mm tear was found on the anterior wall of the common bile duct. The patient recovered without complications after T-tube drainage and cholecystectomy. In this patient none of the factors thought to cause spontaneous rupture of the common bile duct were present, so the authors conclude that the case may be classified as idiopathic spontaneous rupture of the common bile duct.


Ethnocultural parent education in Canada: current status and directions.
The delivery of parent education services to families from ethnocultural communities in Canada is considered. Despite the increased recognition of the importance of matching programs to the needs of participants, an extensive review of the literature revealed only five published studies evaluating parent education programs within ethnocultural communities. Because it was hypothesized that ethnocultural parent education programs exist in Canada despite the paucity of published data, community and tertiary care organizations were surveyed regarding their efforts in this area. The majority of service providers that responded to the survey indicated they do employ special provisions for parents from ethnocultural communities. The most frequently endorsed provisions included: addressing cultural issues within the program curriculum, utilizing ethnocultural facilitators, and offering the program in the first language of the participants. Future directions that follow from the findings are discussed. In particular, the need for empirical evaluation regarding the utility and acceptability of these cultural provisions is stressed.


Oral and inhaled corticosteroid use and risk of recurrent pulmonary embolism.
Chronic inflammatory diseases predispose for development of a first pulmonary embolism (PE). Previous studies showed that corticosteroids, which are the mainstay of treatment for inflammatory diseases, enhance the risk of a first venous thromboembolism. Yet, it is unknown whether corticosteroids also predispose for recurrent events. Therefore, we investigated the association between oral and/or inhaled corticosteroid use and the risk of recurrent PE. We performed a nested case-control study using the PHARMO Database. Adult patients who had suffered from a first PE for which vitamin K antagonists were prescribed, were eligible. Of these, 384 patients with recurrent PE were matched to 1030 patients without recurrent PE. We showed that oral or inhaled corticosteroids was ever used by 22.7% and 20.6% of patients with recurrent PE, and 23.5% and 21.5% of the patients without recurrent PE. There was an overall association between oral corticosteroid use and the risk of recurrent PE (p=0.02). Current use of oral corticosteroids increased the risk of recurrent PE (OR 3.74; 95% CI 2.04-6.87), whereas past use reduced the risk (OR 0.46; 95% CI 0.28-0.74). A similar pattern was observed for inhaled corticosteroids, although less strong (p=0.10). Current use of oral corticosteroids is associated with increased risk of recurrent PE. Whether this increased risk is caused by oral corticosteroids themselves, or by the underlying disease, or both, needs further investigation. Nevertheless, given the frequent use of corticosteroids in clinical practice, clinicians should be aware of this risk.


Macrogeographic population structuring in the cosmopolitan agricultural pest Bactrocera cucurbitae (Diptera: Tephritidae).
The macrogeographic population structure of the agricultural pest Bactrocera cucurbitae (Diptera: Tephritidae) was investigated in order to identify the geographic origin of the species and reconstruct its range expansion. Individuals of B. cucurbitae were collected from 25 worldwide-distributed localities (n = 570) and genotyped at 13 microsatellite loci. The Bayesian clustering reveals that B. cucurbitae can be subdivided into five main groups corresponding to populations from (i) the African continent, (ii) La Réunion, (iii) Central Asia, (iv) East Asia and (v) Hawaii. The proportions of inter-regional assignments and the higher values of genetic diversity in populations from Pakistan, India and Bangladesh suggest that B. cucurbitae originated in Central Asia and expanded its range to East Asia and Hawaii on one hand and to Africa and the islands of the Indian Ocean on the other. A number of outliers (10-19 specimens according to different clustering algorithms) show high levels of admixture (Q > 0.70) with populations from different regions and reveal complex patterns of inter-regional gene flow. Anthropogenic transport is the most plausible promoter of this large-scale dispersal. The introduction of individuals from geographically distant sources did not have a relevant role in the most recent African invasions, which originated from the expansion of local populations. These results could provide a useful background to better evaluate invasion risks and establish priorities for the management of this cosmopolitan agricultural pest.


Efficacy and safety of nephron-sparing surgery.
To analyse the current evidence of efficacy and safety of nephron-sparing surgery (NSS) that encompasses open partial nephrectomy (OPN), laparoscopic partial nephrectomy (LPN) and robotic partial nephrectomy in the management of localized renal cell carcinoma (RCC). Oncological data, complications and postoperative renal function were reviewed for the most important series of partial nephrectomy. Partial nephrectomy (PN) provides similar oncological control as radical nephrectomy (RN) and is superior to RN with respect to preserving renal function and preventing chronic kidney disease. OPN remains the first treatment option for T1 renal tumors in centers without advanced laparoscopic expertise. Indications for LPN have expanded as such that LPN is suited for most renal tumors provided that the procedure is carried out in selected patients by an experienced laparoscopic surgeon. Warm ischemia time should be kept within 20 min, which is currently recommended regardless of surgical approach. In experienced hands, LPN yields intermediate oncological efficacy and renal function outcome comparable to open surgery in the treatment of pT1 renal tumors. Positive surgical margin rates are comparable after LPN and OPN. In contemporary series, the morbidity of LPN is decreasing to become similar to that of OPN. Preliminary results with robotic PN are comparable to results obtained with LPN. Additional studies are required to validate these results and compare with other current methods, such as thermal ablation. NSS is effective and safe for the management of localized RCC and is the gold standard to which new ablative techniques need to be compared.


Perceptions of Pain, Injury, and Transition-Retirement: The Experiences of Professional Dancers.
Dancers are often referred to as "athletes of the arts," and like other athletes they undergo years of hard physical training in pursuit of excellence. Previous research has indicated that dancers develop high pain thresholds and push past their pain barriers. This has potential implications for their health and wellbeing in both their professional careers and life after dance. Therefore, the purpose of this pilot study was to explore the perceptions and experiences of injury, pain, and retirement among professional dancers. Twenty professional dancers, 10 from the United Kingdom and Canada, hereafter referred to as "international," and 10 from Australia participated in a semi-structured interview reflecting on their experiences of the aforementioned issues. The following themes were identified: 1. the injured dancer: the reality; 2. dancers' perceptions and experiences of pain; 3. the transition leading to retirement; and 4. life after dance: attributes facilitating career change. Results from both Australian and international dancers revealed that they withstand, manage, and dance through persistent levels of pain and injury. All participants reported that they were highly motivated and dedicated to their dance careers; however, the majority of Australian dancers were not adequately prepared for, or aware of, the challenges of transition into their post-professional dance lives when compared to the international dancers. Dancer transition organizations currently operate in America, the Netherlands, Canada, and the United Kingdom and serve as valuable models that could be replicated in Australia. The current study recommends increased awareness of pain management and injury prevention strategies for dancers and further supports the rationale for development and implementation of transition models for dancers in Australia and elsewhere.


Synergy of licorice extract and pea protein hydrolysate for oxidative stability of soybean oil-in-water emulsions.
Previously developed radical-scavenging pea protein hydrolysates (PPHs) prepared with Flavourzyme (Fla-PPH) and Protamex (Pro-PPH) were used as cosurfactants with Tween 20 to produce soybean oil-in-water (O/W) emulsions, and the suppression of lipid oxidation was investigated. Both PPHs significantly retarded oxidation (P < 0.05) of the emulsions when stored at 37 °C for 14 days. Electron microscopy revealed an interfacial peptidyl membrane around oil droplets, which afforded steric restrictions to oxidation initiators. When licorice extract (LE) was also used in emulsion preparation, a remarkable synergistic oxidation inhibition was observed with both PPHs. LE adsorbed onto oil droplets either directly or through associating with PPH to produce a thick and compact interfacial membrane enabling the defense against oxygen species. Liquiritin apioside, neolicuroside, glabrene, and 18β-glycyrrhetic acid were the predominant phenolic derivatives partitioning at the interface and most likely the major contributors to the notable synergistic antioxidant activity when coupled with PPHs.


Altered subcellular localization of heat shock protein 90 is associated with impaired expression of the aryl hydrocarbon receptor pathway in dogs.
The aryl hydrocarbon receptor (AHR) mediates biological responses to toxic chemicals. An unexpected role for AHR in vascularization was suggested when mice lacking AHR displayed impaired closure of the ductus venosus after birth, as did knockout mice for aryl hydrocarbon receptor interacting protein (AIP) and aryl hydrocarbon receptor nuclear translocator (ARNT). The resulting intrahepatic portosystemic shunts (IHPSS) are frequently diagnosed in specific dog breeds, such as the Irish wolfhound. We compared the expression of components of the AHR pathway in healthy Irish wolfhounds and dogs with IHPSS. To this end, we analyzed the mRNA expression in the liver of AHR,AIP, ARNT, and other genes involved in this pathway, namely, those for aryl hydrocarbon receptor nuclear translocator 2 (ARNT2), hypoxia inducible factor 1alpha (HIF1A), heat shock protein 90AA1 (HSP90AA1), cytochromes P450 (CYP1A1, CYP1A2, and CYP1B1), vascular endothelial growth factor A (VEGFA), nitric oxide synthesase 3 (NOS3), and endothelin (EDN1). The observed low expression of AHR mRNA in the Irish wolfhounds is in associated with a LINE-1 insertion in intron 2, for which these dogs were homozygous. Down regulation in Irish wolfhounds was observed for AIP, ARNT2, CYP1A2, CYP1B1 and HSP90AA1 expression, whereas the expression of HIF1A was increased. Immunohistochemistry revealed lower levels of AHR, HIF1A, and VEGFA protein in the nucleus and lower levels of ARNT and HSP90AA1 protein in the cytoplasm of the liver cells of Irish wolfhounds. The impaired expression of HSP90AA1 could trigger the observed differences in mRNA and protein levels and therefore explain the link between two very different functions of AHR: regulation of the closure of the ductus venosus and the response to toxins.


Regional progress towards hepatitis C elimination in the Western Pacific Region, 2015-2020.
Chronic hepatitis C (HCV) infection is a major global public health threat and in 2019 there were an estimated 58 million infected globally and 290,000 deaths. Elimination of viral hepatitis B/C as a public health threat by 2030 is defined as a 90% incidence reduction and a 65% mortality reduction. The Western Pacific region is one of the most affected regions with 10 million people living with HCV, one-fifth of the global burden. We review progress towards HCV elimination in the Western Pacific region since 2015. Key developments in the region, which comprises of 37 high-and-middle-income countries, include the following: 20 countries have national hepatitis action plans, 19 have conducted recent disease burden and investment cases, 10 have scaled-up hepatitis services at primary health care level, and in 11 countries, domestic financing including social health insurance support DAA costs. We highlight six countries' experience in navigating the path towards HCV elimination: Cambodia, China, Malaysia, Mongolia, Philippines, and Viet Nam. Future initiatives to accelerate elimination are expanding access to community-based testing using HCV point-of-care tests among at-risk and general populations; adopting decentralized and integrated HCV one-stop services at harm reduction sites, detention settings and primary care; expanding treatment to include children and adolescents; address stigma and discrimination; and ensuring sustainable financing through domestic resources to scale-up testing, treatment and prevention. The COVID-19 pandemic has a significant impact on hepatitis response across the region on community and facility-based testing, treatment initiation, monitoring and cancer screening, which is projected to delay elimination goals.


[Ultrastructural changes in the autonomic interneuronal synapse during activation in the presence of acetylcholinesterase suppression].
Structural-functional reconstructions of the frog autonomic interneuronal synapsis have been studied at its activation with endogenic acetylcholine under conditions of acetylcholinesterase suppression. The investigation has been performed with preparations of isolated sympathetic trunk of Rana temporaria treated with armine (5 X 10(-6) M) and subjected to electrostimulation (5 imp/sec) up to a complete block of the synaptic transmission. Certain structural changes are revealed in the axo-somatic synapses, demonstrating an increased adhesive properties of the membranes, ("hatch-like" membranes, numerous submembranous aggregates, aggregates of the intercellular cleft and neuronal-glial contacts). In the terminals changed according to the "light type", with poorly manifested changes, light synaptic vesicles loose their spheric form, their diameter decreases. In the boutons with more intensive changes, the vesicles gradually change into the mass of cluster-floccular material. In the boutons with intensively manifested disorders in the ultrastructure, a complete destruction of the light vesicles is observed. The great part of the ganglionic neuron bodies changes according the "dark type". In their neuroplasm a great amount of subsuperficial cisterns of the endoplasmic reticulum and formation of powerful fasciculi of microfilaments are noted to appear.


[Pulmonary vein isolation with the cryoballoon technique in atrial fibrillation treatment: single centre experience].
Pulmonary vein (PV) isolation with cryothermal energy is a recently introduced technique in patients with atrial fibrillation (AF). It may reduce procedural times and serious complications associated with radiofrequency (RF) ablation. We aimed to present the baseline characteristics and follow-up data of our study population undergoing cryoballoon AF ablation. A total of 236 patients (126 male, 110 female; mean age 54.6±10.45; range 16 to 78 years) underwent PV isolation with 28 mm cryoballoon due to symptomatic AF. These patients failed with at least one previous antiarrhythmic drug. The postprocedure in the first 3 months was defined as blanking period. Median follow-up time was 14 (3-24) months. Procedural success, complicaitons, and follow-up results were defined according to Heart Rhythm Society guidelines. Acute procedural success rate (>=3 PV isolation) was 99.5%. Mean procedural and fluoroscopy times were 72.5±5.3 (50-90) min and 14±3.5 (12-24) min. Major complications were observed in 3 patients (1.2%). At the median 14 month follow-up, 80.6% of paroxysmal AF patients and 49.2% of persistant AF patients were free from AF recurrence. RF ablation was performed in 10 patients with recurrence. Smoking, body mass index, non-paroxysmal AF type, AF duration (years), left atrial size, and early recurrence were the predictors of recurrence in multivariate regression analysis. This study represents the first experience with cryoballoon ablation for AF in Turkey. The efficacy and safety of cryoballoon AF ablation technique was shown due to the acceptable success and low complication rates in paroxysmal AF patients. Particularly, patients with early recurrence should be closely followed-up.


Effect of Moxidectin on Bed Bug Feeding, Development, Fecundity, and Survivorship.
The common bed bug, Cimex lectularius L. (Hemiptera: Cimicidae), is a blood-feeding ectoparasite which experienced world-wide resurgence during recent decades. The control of bed bugs is often challenging, due to their cryptic nature and resistance to commonly used insecticides. In this study, we evaluated the effect of the antiparasitic drug moxidectin on bed bug survival, reproduction, and development. The LC50 (lethal concentration to kill half the members of a tested population) of moxidectin against bed bug male adults, female adults, and large nymphs were 52.7 (95% CI (confidence interval): 39.5-70.8), 29.3 (95% CI: 20.7-40.5), and 29.1 ng/mL (95% CI: 23.3-35.3), respectively. Moxidectin (≥ 25 ng/mL) reduced egg laying of bed bug females, but showed no significant effect on egg hatching. One time feeding on rabbit blood containing 20 and 40 ng/mL moxidectin showed no negative effects in bed bug feeding and blood meal ingestion, but significantly reduced digestion rates and nymph molting rates. Although moxidectin at concentrations of 20 and 40 ng/mL only caused moderate mortality in bed bugs, it significantly interrupted digestion, development, and oviposition of survived bed bugs for at least one week after feeding. Moxidectin is a promising supplement of the existing bed bug control materials if its use on humans can be approved in the future.


Resistance to Phytophthora cinnamomi in American Chestnut (Castanea dentata) Backcross Populations that Descended from Two Chinese Chestnut (Castanea mollissima) Sources of Resistance.
Restoration of American chestnut (Castanea dentata) depends on combining resistance to both the chestnut blight fungus (Cryphonectria parasitica) and Phytophthora cinnamomi, which causes Phytophthora root rot, in a diverse population of C. dentata. Over a 14-year period (2004 to 2017), survival and root health of American chestnut backcross seedlings after inoculation with P. cinnamomi were compared among 28 BC3, 66 BC4, and 389 BC3F3 families that descended from two BC1 trees (Clapper and Graves) with different Chinese chestnut grandparents. The 5% most resistant Graves BC3F3 families survived P. cinnamomi infection at rates of 75 to 100% but had mean root health scores that were intermediate between resistant Chinese chestnut and susceptible American chestnut families. Within Graves BC3F3 families, seedling survival was greater than survival of Graves BC3 and BC4 families and was not genetically correlated with chestnut blight canker severity. Only low to intermediate resistance to P. cinnamomi was detected among backcross descendants from the Clapper tree. Results suggest that major-effect resistance alleles were inherited by descendants from the Graves tree, that intercrossing backcross trees enhances progeny resistance to P. cinnamomi, and that alleles for resistance to P. cinnamomi and C. parasitica are not linked. To combine resistance to both C. parasitica and P. cinnamomi, a diverse Graves backcross population will be screened for resistance to P. cinnamomi, survivors bred with trees selected for resistance to C. parasitica, and progeny selected for resistance to both pathogens will be intercrossed.


Adenine + thymine content of different genes located on the broad host range plasmid RP4.
The genetic map of plasmid RP4 was correlated with its adenine+thymine (AT) map. For this purpose, RP4 DNA was digested with one or both of the restriction enzymes EcoRI and HindIII and the resulting linear RP4 molecules and fragments were partially denatured, examined in the electron microscope and their AT maps were determined using a computer program. From these AT maps the EcoRI and HindIII restriction sites were located on the AT map of RP4. Since the positions of these restriction sites on the genetic map of RP4 are known, the maps could be compared. They revealed a high AT content for the Tn1 transposon and the kanamycin resistance gene. The tra-1 region is also distinguished by a sharply defined AT-rich region, whereas tra-2 and the tetracycline resistance gene have an AT content which is not distinctly different from the average AT content of RP4.


Functional association of retinoic acid and hedgehog signaling in Xenopus primary neurogenesis.
Previous work has shown that the posteriorising agent retinoic acid can accelerate anterior neuronal differentiation in Xenopus laevis embryos (Papalopulu, N. and Kintner, C. (1996) Development 122, 3409-3418). To elucidate the role of retinoic acid in the primary neurogenesis cascade, we investigated whether retinoic acid treatment of whole embryos could change the spatial expression of a set of genes known to be involved in neurogenesis. We show that retinoic acid expands the N-tubulin, X-ngnr-1, X-MyT1, X-&Dgr;-1 and Gli3 domains and inhibits the expression of Zic2 and sonic hedgehog in the neural ectoderm, whereas a retinoid antagonist produces opposite changes. In contrast, sonic and banded hedgehog overexpression reduced the N-tubulin stripes, enlarged the neural plate at the expense of the neural crest, downregulated Gli3 and upregulated Zic2. Thus, retinoic acid and hedgehog signaling have opposite effects on the prepattern genes Gli3 and Zic2 and on other genes acting downstream in the neurogenesis cascade. In addition, retinoic acid cannot rescue the inhibitory effect of Notch(ICD), Zic2 or sonic hedgehog on primary neurogenesis. Our results suggest that retinoic acid acts very early, upstream of sonic hedgehog, and we propose a model for regulation of differentiation and proliferation in the neural plate, showing that retinoic acid might be activating primary neurogenesis by repressing sonic hedgehog expression.


DNA damage signatures in peripheral blood cells as biomarkers in prodromal huntington disease.
Easily accessible biomarkers in Huntington disease (HD) are actively searched. We investigated telomere length and DNA double-strand breaks (histone variant pγ-H2AX) as predictive disease biomarkers in peripheral blood mononuclear cells (PBMC) from 25 premanifest subjects, 58 HD patients with similar CAG expansion in the huntingtin gene (HTT), and 44 healthy controls (HC). PBMC from the pre-HD and HD groups showed shorter telomeres (p < 0.0001) and a significant increase of pγ-H2AX compared to the controls (p < 0.0001). The levels of pγ-H2AX correlated robustly with the presence of the mutated gene in pre-HD and HD. The availability of a potentially reversible biomarker (pγ-H2AX) in the premanifest stage of HD, negligible in HC, provides a novel tool to monitor premanifest subjects and find patient-specific drugs. Ann Neurol 2018;00:1-6 ANN NEUROL 2019;85:296-301.


Resident interest in physical medicine and rehabilitation fellowships. Results of a survey.
Physiatry, one of the six medical specialties that does not currently offer added or special qualification certification examinations, does not have accredited fellowships in potential subspecialty areas. These issues are currently being debated by the leadership organizations within physical medicine and rehabilitation such as the Association of Academic Physiatrists, the American Academy of Physical Medicine and Rehabilitation, the Physical Medicine and Rehabilitation Residency Review Committee and the American Board of Physical Medicine and Rehabilitation. Recent events, such as the establishment of funding agencies with an interest in medical rehabilitation research training, suggest that physiatric fellowships may become more available. A survey was conducted to determine whether physiatric residents desire postresidency training and, if interested, what type of additional training they would seek. This information could be used in formulating policies regarding the establishment, accreditation and certification of subspecialty fellowships within physical medicine and rehabilitation. Of 968 physiatric residents currently in training, 525 (54%) responded to a 22-question survey assessing resident interest regarding fellowship training, the different subspecialty areas, salary expectations, fellowship duration, preferred amount of time devoted to clinical v research work, mentorship, double boarding, accreditation, certification and a section for general comments. The results of the survey indicate considerable interest in fellowship training, which diminishes as residents approach graduation. Residents favored clinically oriented fellowships of 1-yr duration, which should be accredited and certified. Sports medicine was identified as the area of greatest subspecialty interest.


Turner syndrome diagnosed in northeastern Malaysia.
Turner syndrome affects about one in 2,000 live-born females, and the wide range of somatic features indicates that a number of different X-located genes are responsible for the complete phenotype. This retrospective study highlights the Turner syndrome cases confirmed through cytogenetic analysis at the Human Genome Centre of Universiti Sains Malaysia, from 2001 to 2006. Lymphocyte cultures were set up using peripheral blood samples, chromosomes were prepared, G-banded, karyotyped and analysed in accordance to guidelines from the International System for Human Cytogenetic Nomenclature. The various karyotype patterns observed were 45,X; 46,X,i, (Xq); 45,X/45,X,+mar; 45,X/46,X,i,(Xq) and 45,X/46,XY. The mean age of our patients with Turner syndrome was 21 years, and the most common clinical features encountered in all these patients were short stature (100 percent), primary amenorrhoea (85.7 percent), absence of secondary sexual characteristics (57.1 percent), scanty pubic and axillary hair (50 percent), webbed neck (42.9 percent), wide carrying angle (42.9 percent), rudimentary uterus with bilateral streak ovaries (42.9 percent), underdeveloped breasts (35.7 percent) and wide-spaced nipples (21.4 percent). Even though there is no causal therapy for Turner syndrome, management and treatment are possible for malformations and conditions associated with it. In addition, counselling of the parents and of the patients themselves are necessary. Hence, establishing an early diagnosis, educating and increasing awareness among doctors, and if possible, a prenatal diagnosis, will help in early intervention, genetic counselling and in improving the quality of life in these patients.


Observations on obesity patterns in tetralogy of Fallot patients from childhood to adulthood.
Obesity is increasingly prevalent, and abnormal body mass index is a risk factor for cardiovascular disease. There are limited data published regarding body mass index and CHD. We tested the hypothesis that body mass index and obesity prevalence are increasing in patients with tetralogy of Fallot over time by analysing time since surgery, age, height, weight, and body mass index among tetralogy of Fallot patients and demographic data from age-matched controls. NYHA class and left ventricular ejection fraction were analysed in adults. Body mass index was categorised into normal, overweight, and obese in this single-centre, retrospective chart review. Data were collected from 137 tetralogy of Fallot patients (71 men:66 women), of whom 40 had body mass index >25 kg/m2. Tetralogy of Fallot patients aged <6 years had lower body mass index (15.9 versus 17.1; p=0.042) until 16-20 years of age (27.4 versus 25.4; p=0.43). For adult tetralogy of Fallot patients, the mean body mass index was 26.5 but not statistically significantly different from the control cohort. Obese adult patients had significantly higher average NYHA class compared with those of normal weight (p=0.03), but no differences in left ventricular ejection fraction by echocardiography (p=0.55) or cardiac MRI (p=0.26) were noted. Lower body mass index was observed initially in tetralogy of Fallot patients, but by late adolescence no significant difference was observed. As adults, tetralogy of Fallot patients with higher body mass index had increased NYHA class but similar left ventricular ejection fraction.


Medication adherence in schizophrenia: exploring patients', carers' and professionals' views.
One of the major clinical problems in the treatment of people with schizophrenia is suboptimal medication adherence. Most research focusing on determinants of nonadherence use quantitative research methods. These studies have some important limitations in exploring the decision-making process of patients concerning medication. In this study we explore factors influencing medication adherence behavior in people with schizophrenia using concept mapping. Concept mapping is a structured qualitative method and was performed in 4 European countries. Participants were 27 patients with schizophrenia, 29 carers, and 28 professionals of patients with schizophrenia. Five clinically relevant themes were identified that affect adherence: medication efficacy, external factors (such as patient support and therapeutic alliance), insight, side effects, and attitudes toward medication. Importance ratings of these factors differed significantly between professionals and carers and patients. Professionals, carers, and patients do not have a shared understanding of which factors are important in patients' medication adherence behavior. Adherence may be positively influenced if professionals focus on the positive aspects of medication, on enhancing insight, and on fostering a positive therapeutic relationship with patients and carers.


Rostral anterior cingulate cortex theta current density and response to antidepressants and placebo in major depression.
To assess whether pretreatment theta current density in the rostral anterior cingulate (rACC) and medial orbitofrontal cortex (mOFC) differentiates responders from non-responders to antidepressant medication or placebo in a double-blinded study. Pretreatment EEGs were collected from 72 subjects with Major Depressive Disorder (MDD) who participated in one of three placebo-controlled trials. Subjects were randomized to receive treatment with fluoxetine, venlafaxine, or placebo. Low-resolution brain electromagnetic tomography (LORETA) was used to assess theta current density in the rACC and mOFC. Medication responders showed elevated rACC and mOFC theta current density compared to medication non-responders (rACC: p=0.042; mOFC: p=0.039). There was no significant difference in either brain region between placebo responders and placebo non-responders. Theta current density in the rACC and mOFC may be useful as a biomarker for prediction of response to antidepressant medication. This is the first double-blinded treatment study to examine pretreatment rACC and mOFC theta current density in relation to antidepressant response and placebo response. Results support the potential clinical utility of this approach for predicting clinical outcome to antidepressant treatments in MDD.


Effect of mutS and recD mutations on Salmonella virulence.
Hybrid derivatives of closely related bacteria may be used to dissect strain-specific functions that contribute to virulence within a host. However, mismatches between DNA sequences are a potent barrier to recombination. Recipients with mutS and recD mutations overcome this barrier, allowing construction of genetic hybrids. To determine whether Salmonella hybrids constructed in a mutS recD host can be used to study virulence, we assayed the effect of mutS and recD mutations on the virulence of Salmonella typhimurium 14028s in mice. Mutants defective in either mutS or recD do not affect the time course or the 50% lethal dose (LD(50)) of the infection. In contrast, the inactivation of both mutS and recD results in a synthetic phenotype which substantially increases the time required to cause a lethal infection without changing the LD(50). This phenotype results from an inability of mutS recD double mutants to rapidly adapt to purine-limiting conditions present within macrophages. Although the disease progression is slower, S. typhimurium mutS recD mutants retain the ability to cause lethal infections, and, thus, hybrids constructed in mutS recD hosts may permit the analysis of virulence factors in a surrogate animal model.


Lip reconstruction following Mohs' surgery: the role for composite resection and primary closure.
Surgical outcomes and patient satisfaction with composite resection and primary closure for the management of upper-lip defects following Mohs' surgery were evaluated. Twenty-seven patients underwent upper-lip reconstruction following Mohs' surgery from 1993 to 1997. Twelve of these patients were selected for this report based on adequate follow-up examinations and photographs. There were nine women and three men with a mean age of 46 years (range, 33 to 70 years). Eleven patients underwent Mohs' surgery for basal cell carcinoma and one patient for squamous cell carcinoma of the upper lip. The defects varied in size and location, often extending beyond a single aesthetic subunit. The reconstruction was performed an average of 7 days after Mohs' surgery (range, 1 to 23 days). In 50 percent of the cases, a full-thickness excision was performed, which included orbicularis oris and inner-lip mucosa. The functional results were graded as near normal to normal in all cases. There were no observed changes in oral continence, eating or speech. Two patients experienced numbness medial to the operative site, but this had no adverse affect on lip function. The aesthetic results were graded as very good to excellent in all cases. Eleven of the 12 patients were satisfied with their lip appearance and function. Conventional wisdom dictates that during reconstruction of upper-lip defects, one should attempt to maintain a majority of the uninvolved tissue for the best result. Although these techniques result in wound closure, they fail to consider lip aesthetics. By using a vertically oriented composite resection of the tipper lip with the additional resection of uninvolved tissue, normal lip architecture is maintained. In our experience, this results in a superior aesthetic and functional result.


Time-lapse imaging of microRNA activity reveals the kinetics of microRNA activation in single living cells.
MicroRNAs (miRNAs) are small, non-coding RNAs that play critical roles in the post-transcriptional regulation of gene expression. Although the molecular mechanisms of the biogenesis and activation of miRNA have been extensively studied, the details of their kinetics within individual living cells remain largely unknown. We developed a novel method for time-lapse imaging of the rapid dynamics of miRNA activity in living cells using destabilized fluorescent proteins (dsFPs). Real-time monitoring of dsFP-based miRNA sensors revealed the duration necessary for miRNA biogenesis to occur, from primary miRNA transcription to mature miRNA activation, at single-cell resolution. Mathematical modeling, which included the decay kinetics of the fluorescence of the miRNA sensors, demonstrated that miRNAs induce translational repression depending on their complementarity with targets. We also developed a dual-color imaging system, and demonstrated that miR-9-5p and miR-9-3p were produced and activated from a common hairpin precursor with similar kinetics, in single cells. Furthermore, a dsFP-based miR-132 sensor revealed the rapid kinetics of miR-132 activation in cortical neurons under physiological conditions. The timescale of miRNA biogenesis and activation is much shorter than the median half-lives of the proteome, suggesting that the degradation rates of miRNA target proteins are the dominant rate-limiting factors for miRNA-mediated gene silencing.


Outcome of coronavirus spectrum infections (SARS, MERS, COVID-19) during pregnancy: a systematic review and meta-analysis.
The aim of this systematic review was to report pregnancy and perinatal outcomes of coronavirus spectrum infections, and particularly coronavirus 2019 (COVID-19) disease because of severe acute respiratory syndrome-coronavirus-2 infection during pregnancy. Medline, Embase, Cinahl, and Clinicaltrials.gov databases were searched electronically utilizing combinations of word variants for coronavirus or severe acute respiratory syndrome or SARS or Middle East respiratory syndrome or MERS or COVID-19 and pregnancy. The search and selection criteria were restricted to English language. Inclusion criteria were hospitalized pregnant women with a confirmed coronavirus related-illness, defined as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), or COVID-19. We used meta-analyses of proportions to combine data and reported pooled proportions, so that a pooled proportion may not coincide with the actual raw proportion in the results. The pregnancy outcomes observed included miscarriage, preterm birth, preeclampsia, preterm prelabor rupture of membranes, fetal growth restriction, and mode of delivery. The perinatal outcomes observed were fetal distress, Apgar score <7 at 5 minutes, neonatal asphyxia, admission to a neonatal intensive care unit, perinatal death, and evidence of vertical transmission. Nineteen studies including 79 hospitalized women were eligible for this systematic review: 41 pregnancies (51.9%) affected by COVID-19, 12 (15.2%) by MERS, and 26 (32.9%) by SARS. An overt diagnosis of pneumonia was made in 91.8%, and the most common symptoms were fever (82.6%), cough (57.1%), and dyspnea (27.0%). For all coronavirus infections, the pooled proportion of miscarriage was 64.7% (8/12; 95% confidence interval, 37.9-87.3), although reported only for women affected by SARS in two studies with no control group; the pooled proportion of preterm birth <37 weeks was 24.3% (14/56; 95% confidence interval, 12.5-38.6); premature prelabor rupture of membranes occurred in 20.7% (6/34; 95% confidence interval, 9.5-34.9), preeclampsia in 16.2% (2/19; 95% confidence interval, 4.2-34.1), and fetal growth restriction in 11.7% (2/29; 95% confidence interval, 3.2-24.4), although reported only for women affected by SARS; 84% (50/58) were delivered by cesarean; the pooled proportion of perinatal death was 11.1% (5/60; 95% confidence interval, 84.8-19.6), and 57.2% of newborns (3/12; 95% confidence interval, 3.6-99.8) were admitted to the neonatal intensive care unit. When focusing on COVID-19, the most common adverse pregnancy outcome was preterm birth <37 weeks, occurring in 41.1% of cases (14/32; 95% confidence interval, 25.6-57.6), while the pooled proportion of perinatal death was 7.0% (2/41; 95% confidence interval, 1.4-16.3). None of the 41 newborns assessed showed clinical signs of vertical transmission. In hospitalized mothers infected with coronavirus infections, including COVID-19, >90% of whom also had pneumonia, preterm birth is the most common adverse pregnancy outcome. COVID-19 infection was associated with higher rate (and pooled proportions) of preterm birth, preeclampsia, cesarean, and perinatal death. There have been no published cases of clinical evidence of vertical transmission. Evidence is accumulating rapidly, so these data may need to be updated soon. The findings from this study can guide and enhance prenatal counseling of women with COVID-19 infection occurring during pregnancy, although they should be interpreted with caution in view of the very small number of included cases.


The Spanish flu in Uppsala, clinical and epidemiological impact of the influenza pandemic 1918-1919 on a Swedish county.
The Spanish flu reached Sweden in June 1918, and at least one-third of the population (then 5.8 million) became infected. Some 34,500 persons (5.9 per 1,000 people) died from influenza during the first year of the pandemic (when acute pneumonia is included, the number of deaths rose to 7.1 per 1,000 people). In this historical look back at the pandemic, our aim was to review the epidemiological impact on the Swedish county of Uppsala, the clinical outcomes and the economic impact on the regional hospital; a relevant backgound to consider the impact of a future virulent pandemic. We also focused on how the pandemic was perceived by the medical community and by health care authorities. Health care reports, statistics, daily newspapers, medical journals, and records of patients treated for influenza at the Uppsala Academic Hospital from July 1918 to June 1919 were included in our review. An influenza related mortality rate of 693 persons (5.1 per 1,000 people) was reported in the Uppsala region from 1918-1919; from July 1918 to June 1919, 384 patients were treated for influenza at the Uppsala Academic Hospital. The first wave peaked in November 1918 with case fatality rates up to 30%; a second wave peaked in April 1919 with a lower rate of mortality. Of the patients treated, a total of 66 died. Of these, 60% were 20-29 years of age, and 85% were less than 40 years old. Autopsy reports revealed pneumonia in 89% of the cases; among these, 47% were hemorrhagic, 18% were bilateral, and 45% had additional extrapulmonary organ involvement. Signs of severe viral disease were documented, but secondary bacterial disease was the primary cause of death in the majority of cases. The epidemiologic and pathologic results were in accordance with other publications of this time period. The costs of running the hospital doubled from 1917 to 1920 and then reversed by 45%. Today, an influenza pandemic of the same virulence would paralyze health care systems and result in extremely high financial costs and rates of mortality.


The oral health status of children undergoing hemodialysis treatment.
In this study, we investigated the oral status of children suffering from end-stage renal disease (ESRD) with the aim of determining the causes of low caries prevalence in this population (using the CRT bacteria and buffer test), and compared results with a control group (n=38). In the study group, there were 38 children (aged 4-17 years) who were being treated in pediatric nephrology units at three different hospitals in Izmir, Turkey. The study and control groups did not significantly differ in daily tooth brushing frequency and periodic dental check-up frequency. Severe enamel hypoplasia was present in the study group. Dmft, DMFT, gingival and plaque indices were compared statistically in mixed dentition stage with the control group and dmft and gingival status showed a statistically significant difference (p<0.05). The differences among groups for DMFT and plaque indices were not statistically significant. In the study group, high salivary buffer capacity was found in 89.5% of patients. Salivary levels of cariogenic streptococcus mutans and lactobacilli in the study group were significantly lower than in the control group. In conclusion, probably due to increased concentrations of antibacterial chemicals such as urea in the saliva of children with ESRD, decreased levels of cariogenic microorganisms were detected. Therefore, although dental treatment need is not high, these children should receive dental health education, including oral hygiene instruction, in order to improve their overall oral health.


National Healthcare Safety Network 2018 Baseline Neonatal Standardized Antimicrobial Administration Ratios.
The microbiologic etiologies, clinical manifestations, and antimicrobial treatment of neonatal infections differ substantially from infections in adult and pediatric patient populations. In 2019, the Centers for Disease Control and Prevention developed neonatal-specific (Standardized Antimicrobial Administration Ratios SAARs), a set of risk-adjusted antimicrobial use metrics that hospitals participating in the National Healthcare Safety Network's (NHSN's) antimicrobial use surveillance can use in their antibiotic stewardship programs (ASPs). The Centers for Disease Control and Prevention, in collaboration with the Vermont Oxford Network, identified eligible patient care locations, defined SAAR agent categories, and implemented neonatal-specific NHSN Annual Hospital Survey questions to gather hospital-level data necessary for risk adjustment. SAAR predictive models were developed using 2018 data reported to NHSN from eligible neonatal units. The 2018 baseline neonatal SAAR models were developed for 7 SAAR antimicrobial agent categories using data reported from 324 neonatal units in 304 unique hospitals. Final models were used to calculate predicted antimicrobial days, the SAAR denominator, for level II neonatal special care nurseries and level II/III, III, and IV NICUs. NHSN's initial set of neonatal SAARs provides a way for hospital ASPs to assess whether antimicrobial agents in their facility are used at significantly higher or lower rates compared with a national baseline or whether an individual SAAR value is above or below a specific percentile on a given SAAR distribution, which can prompt investigations into prescribing practices and inform ASP interventions.


Dog ownership satisfaction determinants in the owner-dog relationship and the dog's behaviour.
Dog ownership satisfaction relates to the quality of life of both owner and dog, and when seriously compromised may even lead to dog abandonment. Knowledge on determinants of dog ownership satisfaction is limited, obstructing solutions for promoting satisfaction, and here we quantified causes making dog owners less than very satisfied with their dog. We focused on the owner perceived relationship with the dog, unwanted dog behaviour, and dog obedience class attendance. The study population included only few seriously dissatisfied dog owners, preventing discrimination of multiple levels below 'very satisfied'. Consequently, existing relationships in the entire population may have been missed or underestimated and the findings apply specifically to dog owners that are relatively contented with dog ownership. Nine hundred seventy-seven Dutch dog owners completed an online questionnaire and we found the probability of being very satisfied to associate with all three subscales of the Monash Dog Owner Relationship Scale. Most strongly with perceived costs of ownership and less so with shared activities between owner and dog, and perceived emotional closeness to the dog. Aggression and/or disobedience related directly to high perceived ownership costs and to an increased probability of being less than very satisfied. Interaction effects indicated that dog disobedience was less influential on ownership satisfaction at high levels of aggression. Surprisingly, dog ownership satisfaction was unrelated to dog obedience class attendance, raising questions about the effectiveness of these classes in establishing satisfying dog-owner relationships. Training aids used during classes could play a role here, as choke chain use associated with high perceived costs and increased probabilities of being less then very satisfied with dog ownership. Ownership satisfaction in relatively contented dog owners, seems more influenced by unwanted dog behaviour and perceived costs of ownership, than by perceived emotional closeness to the dog, shared activities and dog obedience class attendance.


High-resolution stress mapping of polycrystalline alumina compression using synchrotron X-ray diffraction.
The ability to achieve uniform stress in uniaxial compression tests of polycrystalline alumina is of significance for the calibration of piezospectroscopic coefficients as well as strength studies in ceramics. In this study high-energy X-rays were used to capture powder diffraction profiles over a half-section of a polycrystalline alumina parallelepiped sample under an increasing uniaxial compressive load. The data were converted to strain and results were used for stress mapping of the sample. Stress maps from the study quantify the higher stresses at the sample-platen contact interface and reveal the evolution of the stress distribution in these specimens with load. For the geometry of the samples used, at the center section of the specimen the overall magnitudes of the compressive stresses were found to be 20% higher compared with the average expected theoretical stress based on the applied load and cross-sectional area. The observed compressive stresses at the corners of the parallelepiped specimen were 62% higher and shear stresses were observed at the specimen interface to the load mechanism. The effects, seen at the interface, can lead to premature failure at these locations and can affect the accuracy of calibration of spectral peaks with stress as well as compression strength measurements. The results provide important information that can be used to establish guidelines on material and geometry considerations in developing compression tests on high-strength ceramics.


Patient information leaflets for Transrectal Ultrasound guided prostate biopsy: Results of North Thames deanery survey.
We evaluated the quality of patient information leaflets for Trans-Rectal Ultrasound guided prostate biopsies (TRUS-Bx) in North Thames region. TRUS-Bx information leaflets were requested from 24 hospitals in the region. All hospitals were contacted by telephone, and non-responders were followed-up by postal survey. Leaflets received were evaluated for a clear description of the procedure, directions to TRUS-Bx location, a clear description of the procedure, contact for queries/concerns, information about preparation prior to procedure, information about regular medication, information on how to obtain results, instructions for follow-up arrangements, analgesia used and risk of morbidity/mortality. Additionally, the leaflets were evaluated for diagrams to clarify the procedure and the anatomy, and sources of additional information, such as reference to published articles or prostate cancer patient support groups/internet websites. In summary, a total of 17 leaflets (77%) were received. Of these, the majority (94%) had a clear description of the procedure, contact for queries/concerns (82%), information about preparation prior to TRUS-Bx (71%). Directions to TRUS-Bx location (29%), and analgesia used (35%), was very poorly described, and information on obtaining results and follow-up arrangements were described in only 12 (71%) leaflets. Complications such as risks of infection, haematuria, haematospermia and rectal bleeding, were generally explained (71%-76% of leaflets), urinary retention was mentioned in only 5 (29%) leaflets and mortality in only 1 case. Descriptive diagrams of the procedure and prostate anatomy were very rarely used, and sources of additional information were limited to 1 published article and reference to 1 prostate cancer support group. This study demonstrates that there is large variation in the information supplied in TRUS-Bx patient information leaflets in the North Thames region, with some leaflets lacking vital information. It is proposed that a standard patient information leaflet incorporating all the factors in the checklist should be designed, with the incorporation of a new BAUS procedure specific consent form for TRUS-Bx.


[TNF-induced apoptosis and necrosis in myeloleukemia cells HL-60 is regulated by reactive oxygen metabolites depending on a cell cycle phase].
TNF is the known death receptor ligand which induce apoptosis and necrosis. Reactive oxygen metabolites, ceramide (synthesized de novo and as a product of sphingomyelin cycle), and caspases have been implicated as potential mediators of cell death. Their mechanistic relationship remains to be elucidated. The presence and activation of executor caspase-3 has been found to be regulated during both TNF-induced apoptosis and necrosis on their early stages. TNF-induced cell damage, suggesting the induction of both, apoptosis and necrosis, depended on the cell cycle. Necrosis induced by TNF was inhibited by denitrophenol (DNP). Pretreatment of these cells with exogenous bacterial sphingomyelinase (SMase) potentiates TNF-alpha induced apoptosis only, suggesting the role of ceramide from sphingomyelin cycle in TNF signaling pathways of apoptosis. DNP was found to initiate necrosis after SMase and TNF common action. The role of ceramide synthesis in enhanced ceramide generation in response to oxidant stress was shown using inhibitor of ceramide synthase--fumonisin B1. Its effect was found to be modulated by mitochondrial chain respiration inhibitors. Monoclonal antibodies to TNF-alpha receptors R1 and R2 exhibit the more high level of necrosis compared with TNF and both regulated by DNP and phospholipase A2. TNF-R2 effect was not found previously. Ceramide synthesis and sphingomyelin breakdown, caspase activation and reactive oxygen metabolites production are required for the TNF-alpha-induced apoptosis and necrosis which may be regulated dependently on cell cycle. TNF-initiated necrosis seems to be the disrupted apoptotic program and may be classified as aponecrosis.


An efficient learning algorithm for associative memories.
Associative memories (AMs) can be implemented using networks with or without feedback. In this paper we utilize a two-layer feedforward neural network and propose a new learning algorithm that efficiently implements the association rule of a bipolar AM. The hidden layer of the network employs p neurons where p is the number of prototype patterns. In the first layer, the input pattern activates at most one hidden layer neuron or "winner." In the second layer, the "winner" associates the input pattern to the corresponding prototype pattern. The underlying association principle is minimum Hamming distance and the proposed scheme can be viewed also as an approximately minimum Hamming distance decoder. Theoretical analysis supported by simulations indicates that, in comparison with other suboptimum minimum Hamming distance association schemes, the proposed structure exhibits the following favorable characteristics: 1) It operates in one-shot which implies no convergence-time requirements; 2) it does not require any feedback; and 3) our case studies show that it exhibits superior performance than the popular linear system in a saturated mode (LSSM). The network also exhibits 4) exponential capacity and 5) easy performance assessment (no asymptotic analysis is necessary). Finally, since it does not require any hidden layer interconnections or tree-search operations, it exhibits low structural as well as operational complexity.


Anticipatory anxiety and participation in cancer screening. A systematic review.
To synthesize current evidence on the association between anticipatory anxiety, defined as apprehension-specific negative affect that may be experienced when exposed to potential threat or uncertainty, and cancer screening to better inform strategies to maximize participation rates. Searches related to cancer screening and anxiety were conducted in seven electronic databases (APA PsycINFO, Scopus, Web of Science, Embase, Cochrane Library, PubMed, CINAHL), with potentially eligible papers screened in Covidence. Data extraction was conducted independently by multiple authors. Barriers to cancer screening for any type of cancer and relationships tested between anticipatory anxiety and cancer screening and intention were categorized and compared according to the form and target of anxiety and cancer types. A total of 74 articles (nparticipants = 119,990) were included, reporting 103 relationships tested between anticipatory anxiety and cancer screening and 13 instances where anticipatory anxiety was reported as a barrier to screening. Anticipatory anxiety related to a possible cancer diagnosis was often associated with increased screening, while general anxiety showed no consistent relationship. Negative relationships were often found between anxiety about the screening procedure and cancer screening. Anticipatory anxiety about a cancer diagnosis may promote screening participation, whereas a fear of the screening procedure could be a barrier. Public health messaging and primary prevention practitioners should acknowledge the appropriate risk of cancer, while engendering screening confidence and highlighting the safety and comfort of screening tests.


Screening for diabetic retinopathy with a mobile non-mydriatic digital fundus camera in southern Israel.
Diabetic retinopathy is a leading cause of adult blindness and accounts for about 10% of cases of legal blindness in Israel. Only about half of the patients with diabetes in Israel have regular eye examinations. To evaluate, for the first time in southern Israel, a new service for diabetic retinopathy screening that uses a mobile non-mydriatic mobile fundus camera in primary care patients. Diabetic members of the largest health fund in southern Israel and over 18 years old were invited for non-mydriatic fundus examination between January and October 2009. Screening was performed by a trained photographer using the Topcon TRC NW-6S non-mydriatic camera in nine primary care centers. A total of 4318 diabetic patients were screened, of whom 53% were classified as normal. The incidence of diabetic retinopathy was 15.8% (1.2% had proliferative retinopathy and 2.4% had suspected macular edema and were referred for laser treatment). Other possible sight-threatening conditions were detected in 9.3%. Fundus pictures were inadequate for assessment in 16% of cases. Diabetic retinopathy screening with a mobile non-mydriatic fundus camera improved the quality of care for diabetic patients in southern Israel. This screening method identified patients requiring prompt referral to the ophthalmologist for further complete eye examination. Extending this screening program to other areas in the country should be considered.


Trends of hypertensive disorders of pregnancy among the Medicaid population before and during COVID-19.
Hypertensive disorders of pregnancy (HDP) are a group of high blood pressure disorders during pregnancy that are a leading cause of maternal and infant morbidity and mortality. The trend of HDP among the Medicaid population during the coronavirus disease of 2019 (COVID-19) is severely lacking. To determine the trends in the annual prevalence of HDP among Louisiana Medicaid pregnant women before and during the COVID-19 pandemic (2016-2021), a total of 113,776 pregnant women aged 15-50 years was included in this study. For multiparous individuals, only the first pregnancy was used in the analyses. Women with a diagnosis of each type-specific HDP were identified by using the ICD-10 codes. The prevalence of HDP increased from 10.5% in 2016 to 17.7% in 2021. The highest race/ethnicity-specific incidence of HDP was seen in African American women (13.1%), then white women (9.4%), followed by other women (7.9%). HDP remains as a very prevalent and significant global health issue, especially in African American women. Obesity and physical inactivity are major risk factors of HDP, which became amplified during the COVID-19 pandemic and led to a higher prevalence of HDP. Severe HDP substantially increases the risk of mortality in offspring and long-term issues in both the mother and infant. This is very pertinent to the Medicaid population due to the disparities and barriers that diminish the quality of healthcare they receive.


Enhancing Ligand Pose Sampling for Molecular Docking.
Deep learning promises to dramatically improve scoring functions for molecular docking, leading to substantial advances in binding pose prediction and virtual screening. To train scoring functions-and to perform molecular docking-one must generate a set of candidate ligand binding poses. Unfortunately, the sampling protocols currently used to generate candidate poses frequently fail to produce any poses close to the correct, experimentally determined pose, unless information about the correct pose is provided. This limits the accuracy of learned scoring functions and molecular docking. Here, we describe two improved protocols for pose sampling: GLOW (auGmented sampLing with sOftened vdW potential) and a novel technique named IVES (IteratiVe Ensemble Sampling). Our benchmarking results demonstrate the effectiveness of our methods in improving the likelihood of sampling accurate poses, especially for binding pockets whose shape changes substantially when different ligands bind. This improvement is observed across both experimentally determined and AlphaFold-generated protein structures. Additionally, we present datasets of candidate ligand poses generated using our methods for each of around 5,000 protein-ligand cross-docking pairs, for training and testing scoring functions. To benefit the research community, we provide these cross-docking datasets and an open-source Python implementation of GLOW and IVES at https://github.com/drorlab/GLOW_IVES .